About TET2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TET2 c.1413C>T, p.(Ser471=)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is present at extremely low frequency in population databases: gnomAD v2.1 AF=0.00142% (4/282,248 alleles), gnomAD v4.1 AF=0.00056% (9/1,614,034 alleles), grpmax FAF=7.04e-06. Absent from gnomAD-Canada. Frequency is well below the 0.1% PM2 threshold for a rare disease variant.
Benign criteria applied · 1
BP7Supporting
BP7 · supporting
This is a synonymous variant (p.Ser471=) for which SpliceAI predicts no impact on splicing (max delta score = 0.00; no donor gain, donor loss, acceptor gain, or acceptor loss). No evidence of cryptic splice site creation. The variant meets BP7 criteria for a silent variant without predicted splice impact.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP7 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
9 / 1,614,034 alleles
gnomAD v4.1: 9 / 1,614,034 alleles. Recorded AF 5.57609e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.41719e-05; MAF= 0.00142%, 4/282248 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.108e-05; MAF= 0.00311%, 4/128700 alleles, homozygotes = 0); grpmax FAF= 7.04e-06.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Likely benign.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 9 not met · 10 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_001127208.2:c.1413C>T (p.Ser471=) is a synonymous variant in TET2 at extremely low population frequency (gnomAD v2.1 AF=0.00142%, 4/282,248 alleles; v4.1 AF=0.00056%, 9/1,614,034 alleles), meeting PM2 at supporting level.
SpliceAI predicts no splicing impact (max delta=0.00), meeting BP7 (supporting benign) for a synonymous variant without predicted splice alteration.
ClinVar contains a single submission classifying this variant as Likely benign (Ambry Genetics, criteria provided), though no expert panel review exists. PS5 and PP5 are not met as the classification is not pathogenic.
No variant-specific literature, functional studies, de novo observations, or segregation data were identified. Multiple criteria could not be assessed due to absence of evidence.
The pathogenic evidence (PM2 supporting) and benign evidence (BP7 supporting_benign) are balanced and of equivalent weight. The variant is classified as a Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 combination rules.
No criteria match.
Met · 2
PM2 SupportingThis variant is present at extremely low frequency in population databases: gnomAD v2.1 AF=0.00142% (4/282,248 alleles), gnomAD v4.1 AF=0.00056% (9/1,614,034 alleles), grpmax FAF=7.04e-06. Absent from gnomAD-Canada. Frequency is well below the 0.1% PM2 threshold for a rare disease variant. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 4/282
- 248 alleles (AF=1.42e-05)
- 0 homozygotes
- grpmax FAF=7.04e-06
- gnomAD v4.1: 9/1
- 614
- 034 alleles (AF=5.58e-06)
- grpmax FAF=2.47e-06
- gnomAD-Canada: absent
- Highest subpopulation AF: European (non-Finnish) 3.11e-05 (v2)
- Remaining 3.20e-05 (v4)
Sources
BP7 SupportingThis is a synonymous variant (p.Ser471=) for which SpliceAI predicts no impact on splicing (max delta score = 0.00; no donor gain, donor loss, acceptor gain, or acceptor loss). No evidence of cryptic splice site creation. The variant meets BP7 criteria for a silent variant without predicted splice impact. Details ▾Hide ▴
Evidence considered
- Synonymous variant: NM_001127208.2:c.1413C>T → NP_001120680.1:p.(Ser471=)
- SpliceAI max delta = 0.00: no predicted donor gain
- donor loss
- acceptor gain
- or acceptor loss
- SpliceAI lookup performed at https://spliceailookup.broadinstitute.org
Still missing
- Nucleotide conservation data not available to confirm the variant position is not highly conserved
Sources
Not met · 9 · evaluated, threshold not reached
PM1 The variant does not lie in a statistically significant mutational hotspot, nor in a critical functional domain where all missense variants are pathogenic. Hotspot analysis: residue_significant=false, exact variant not listed. Details ▾Hide ▴
Evidence considered
- Hotspot analysis: residue S471 is not a statistically significant hotspot
- exact variant not listed in cancer hotspot databases
PP3 Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no splice impact (max delta=0.00). REVEL and BayesDel scores are not available for this synonymous variant. No in silico tool predicts pathogenicity. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta score = 0.00
- no predicted donor gain
- donor loss
- acceptor gain
- or acceptor loss
- REVEL: not found (synonymous variant
- not scored by REVEL)
- BayesDel: not found (synonymous variant)
- HCI prior: not found (gene TET2 not supported)
Sources
PP5 PP5 requires a reputable source to have classified the variant as pathogenic. The only ClinVar submission classifies this variant as Likely benign (Ambry Genetics, single submitter). No expert panel classification as pathogenic exists. Details ▾Hide ▴
Evidence considered
- ClinVar VariationID 3806053: Likely benign
- criteria provided
- single submitter (Ambry Genetics
- SCV005954740)
Sources
BA1 BA1 threshold is >1% allele frequency. gnomAD v2.1 AF=0.00142% (4/282,248 alleles), gnomAD v4.1 AF=0.00056% (9/1,614,034 alleles). Both are well below the 1% threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=1.42e-05 (0.00142%)
- 4/282
- 248 alleles
- gnomAD v4.1 AF=5.58e-06 (0.00056%)
- 9/1
- 614
- 034 alleles
Sources
BS1 BS1 threshold is >0.3% allele frequency. gnomAD v2.1 AF=0.00142% and gnomAD v4.1 AF=0.00056% are both well below the 0.3% threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=1.42e-05 (0.00142%)
- 4/282
- 248 alleles
- gnomAD v4.1 AF=5.58e-06 (0.00056%)
- 9/1
- 614
- 034 alleles
Sources
BP4 BP4 requires multiple lines of computational evidence suggesting no impact. Only SpliceAI (max delta=0.00) is available, which is a single line of evidence. REVEL, BayesDel, and HCI prior are not available for this variant. Conservation data is not available. A single computational datum is insufficient to satisfy the 'multiple lines' requirement of BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta = 0.00 (single line of evidence
- insufficient for BP4 'multiple lines' requirement)
- REVEL: not found
- BayesDel: not found
- HCI prior: not found
Still missing
- No conservation data available to provide second line of benign computational evidence
Sources
BP5 BP5 applies when a variant has not been observed in affected individuals despite being present in a case with an alternate molecular basis. This variant has been observed in a clinical testing context (ClinVar submission SCV005954740, Ambry Genetics), indicating it has been encountered in a diagnostic setting. BP5 is not met. Details ▾Hide ▴
Evidence considered
- ClinVar SCV005954740: variant observed in clinical testing by Ambry Genetics
Sources
BP6 BP6 applies when a reputable source reports the variant as benign and the evidence is not available for independent evaluation. Independent evaluation has been performed using available evidence (gnomAD, SpliceAI, ClinVar). The sole ClinVar classification is Likely benign from a single submitter (Ambry Genetics) without expert panel review; this does not independently meet the BP6 threshold. Details ▾Hide ▴
Evidence considered
- ClinVar VariationID 3806053: Likely benign
- single submitter (Ambry Genetics)
- criteria provided
- Independent evaluation performed with available evidence
Sources
PS5 PS5 requires a reputable source to have classified the variant as pathogenic. The only ClinVar submission classifies this variant as Likely benign (Ambry Genetics, criteria provided, single submitter). No expert panel or multi-submitter pathogenic classification exists. Details ▾Hide ▴
Evidence considered
- ClinVar VariationID 3806053: Likely benign by Ambry Genetics (SCV005954740)
- criteria provided
- single submitter
Sources
Not assessed · 10 · no assessment recorded
PS2 No de novo evidence identified. ClinVar submission audit and literature search yielded no de novo observations for this variant. Details ▾Hide ▴
Still missing
- No de novo testing data available for this variant
PS3 No functional study data available for this variant. REVEL and BayesDel scores not available for synonymous variants. No variant-specific functional evidence identified in ClinVar submissions or literature. Details ▾Hide ▴
Still missing
- No functional studies assessing the impact of c.1413C>T on TET2 expression
- splicing
- or function
PS4 No case-control or affected-cohort enrichment data available. ClinVar contains a single submitter classification (Ambry Genetics, Likely benign) from clinical testing but no affected-person counts or case-control comparisons. Details ▾Hide ▴
Evidence considered
- ClinVar VariationID 3806053: single clinical testing submission
- Likely benign
- no affected counts
Still missing
- No case-control data or affected-cohort prevalence data for c.1413C>T
Sources
PM6 No de novo data available. No de novo observations identified in ClinVar submissions or literature for this variant. Details ▾Hide ▴
Still missing
- No de novo testing data available
PP1 No family segregation data available for this variant. Details ▾Hide ▴
Still missing
- No co-segregation data
PP4 No detailed phenotype data available for individuals carrying this variant. Single ClinVar submission from Ambry Genetics does not include phenotype specifics. Details ▾Hide ▴
BS2 Variant is present in gnomAD at very low frequency (4 alleles v2.1, 9 alleles v4.1) but the health status of these individuals is unknown. TET2 germline disease (ALPS-like phenotype with hematologic malignancy) has variable penetrance; observation in population databases alone is insufficient to confirm observation in a confirmed healthy adult with full expected penetrance. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 4 carriers
- no health-status data
- gnomAD v4.1: 9 carriers
Still missing
- Health status of gnomAD carriers unknown
- no systematic healthy-adult cohort data available
Sources
BS3 No functional studies demonstrating no deleterious effect for this variant. No variant-specific functional evidence available. Details ▾Hide ▴
Still missing
- No functional studies assessing the benign impact of c.1413C>T
BS4 No family segregation data available. Lack of segregation in affected family members cannot be assessed without pedigree data. Details ▾Hide ▴
Still missing
- No segregation data to evaluate lack of co-segregation with disease
BP2 No data on observations of this variant in trans with a pathogenic variant. TET2 germline disease follows an autosomal dominant (heterozygous LoF) model; BP2 primarily applies to recessive disorders. Details ▾Hide ▴
Still missing
- No data on in trans observations
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ASynonymous variant (p.Ser471=) does not meet null-variant criteria. PVS1 requires nonsense, frameshift, canonical splice, initiation codon, or exon deletion variants per ClinGen PVS1 framework (PMC6185798). Details ▾Hide ▴
Evidence considered
- Variant is synonymous: NM_001127208.2:c.1413C>T
- NP_001120680.1:p.(Ser471=)
- Variant bucket 'other' — not a null variant per ClinGen PVS1 decision tree
- apply_generic_pvs1_framework: false
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 N/ASynonymous variant produces no amino acid change. PS1 requires the same amino acid change as a known pathogenic variant, which is not applicable to synonymous substitutions. Details ▾Hide ▴
Evidence considered
- Protein consequence: NP_001120680.1:p.(Ser471=) — no amino acid change
PM3 N/ATET2 germline disease follows an autosomal dominant model (heterozygous LoF); PM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AVariant is a single-nucleotide synonymous substitution, not an in-frame deletion/insertion or stop-loss variant. Details ▾Hide ▴
No further detail was recorded.
PM5 N/ASynonymous variant (p.Ser471=) produces no amino acid change. PM5 requires a different missense change at the same residue as a known pathogenic missense variant, which is not applicable to synonymous substitutions. Details ▾Hide ▴
Evidence considered
- pm5_candidates: eligible_for_classic_pm5_search=false
- unable to parse missense residue context from p.(Ser471=)
Sources
pm5_candidates
PP2 N/ASynonymous variant, not missense. PP2 is applicable only to missense variants in a gene with a low rate of benign missense variation and where missense variants are a common disease mechanism. Details ▾Hide ▴
Evidence considered
- Protein consequence: NP_001120680.1:p.(Ser471=) — no amino acid change
BP1 N/ASynonymous variant, not missense. BP1 applies specifically to missense variants in a gene where a truncating mechanism is the primary cause of disease. Details ▾Hide ▴
Evidence considered
- Protein consequence: NP_001120680.1:p.(Ser471=) — no amino acid change
BP3 N/AVariant is not an in-frame insertion/deletion in a non-repeat region. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- TET2
- Transcript
- NM_001127208.2
- Coding (HGVS c.)
- NM_001127208.2:c.1413C>T
- Protein (HGVS p.)
- NP_001120680.1:p.(Ser471=)
- GRCh38
- chr4:105235355 C>T
- GRCh37
- chr4:106156512 C>T
- ClinVar
- 3806053
Gene diagram
Every interpreted variant in TET2, mapped onto the exon structure of NM_001127208.2. Select a row to find it on the plot.
TET2NM_001127208.2
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in TET2
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
9 / 1,614,034 alleles
AF 5.58e-06 · 0 homozygotes · FAF 2.47e-06
gnomAD v2.1
4 / 282,248 alleles
AF 1.42e-05 · 0 homozygotes · FAF 7.04e-06
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 5.6e-06 · 9 / 1,614,034 alleles · 0 hom · FAF 2.5e-06
| Remaining individuals2 / 62,486 | 3.2e-05 |
| European (non-Finnish)7 / 1,180,018 | 5.9e-06 |
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 1.4e-05 · 4 / 282,248 alleles · 0 hom · FAF 7e-06
| European (non-Finnish)4 / 128,700 | 3.1e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 5.57609e-06; MAF= 0.00056%, 9/1614034 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 3.20072e-05; MAF= 0.00320%, 2/62486 alleles, homozygotes = 0); grpmax FAF= 2.47e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.41719e-05; MAF= 0.00142%, 4/282248 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.108e-05; MAF= 0.00311%, 4/128700 alleles, homozygotes = 0); grpmax FAF= 7.04e-06.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP7 SupportingThis is a synonymous variant (p.Ser471=) for which SpliceAI predicts no impact on splicing (max delta score = 0.00; no donor gain, donor loss, acceptor gain, or acceptor loss). No evidence of cryptic splice site creation. The variant meets BP7 criteria for a silent variant without predicted splice impact. Details ▾Hide ▴
Evidence considered
- Synonymous variant: NM_001127208.2:c.1413C>T → NP_001120680.1:p.(Ser471=)
- SpliceAI max delta = 0.00: no predicted donor gain
- donor loss
- acceptor gain
- or acceptor loss
- SpliceAI lookup performed at https://spliceailookup.broadinstitute.org
Still missing
- Nucleotide conservation data not available to confirm the variant position is not highly conserved
Sources
PP3 Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no splice impact (max delta=0.00). REVEL and BayesDel scores are not available for this synonymous variant. No in silico tool predicts pathogenicity. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta score = 0.00
- no predicted donor gain
- donor loss
- acceptor gain
- or acceptor loss
- REVEL: not found (synonymous variant
- not scored by REVEL)
- BayesDel: not found (synonymous variant)
- HCI prior: not found (gene TET2 not supported)
Sources
BP4 BP4 requires multiple lines of computational evidence suggesting no impact. Only SpliceAI (max delta=0.00) is available, which is a single line of evidence. REVEL, BayesDel, and HCI prior are not available for this variant. Conservation data is not available. A single computational datum is insufficient to satisfy the 'multiple lines' requirement of BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta = 0.00 (single line of evidence
- insufficient for BP4 'multiple lines' requirement)
- REVEL: not found
- BayesDel: not found
- HCI prior: not found
Still missing
- No conservation data available to provide second line of benign computational evidence
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
9 / 1,614,034 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
1 Likely benign
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/3806053/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/4-106156512-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr4-105235355-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/4-105235355-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001127208.2%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/TET2/S471=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=TET2+c.1413C%3ET
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 5.57609e-06; MAF= 0.00056%, 9/1614034 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 3.20072e-05; MAF= 0.00320%, 2/62486 alleles, homozygotes = 0); grpmax FAF= 2.47e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.41719e-05; MAF= 0.00142%, 4/282248 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.108e-05; MAF= 0.00311%, 4/128700 alleles, homozygotes = 0); grpmax FAF= 7.04e-06.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory). (ClinVarID = 3806053)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.